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Abstract Number: 298

Investigating the Pathogenic Role of ER Stress Pathway Activation in the Idiopathic Inflammatory Myopathies (IIM): Skeletal Muscle Cells As a Source of Cytokines (Myokines)

Adam P. Lightfoot1, Katarzyna Goljanek-Whysall2, Kate E. Earl2, Caroline V. Cotton2, Anne McArdle1 and Robert G. Cooper3, 1Musculoskeletal Biology, University of Liverpool, Liverpool, United Kingdom, 2University of Liverpool, Liverpool, United Kingdom, 3Rheumatic Diseaes Center, Salford Royal Foundation Trust, University of Manchester, Salford, United Kingdom

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: cytokines, ER Stress, myositis and polymyositis/dermatomyositis (PM/DM)

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Session Information

Date: Sunday, November 8, 2015

Title: Muscle Biology, Myositis and Myopathies Poster

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: The idiopathic inflammatory myopathies (IIM) are a collection of autoimmune disorders, characterised by the development of debilitating symmetrical skeletal muscle weakness. IIM Patients also have elevated creatine kinase levels with an array of circulating myositis-specific autoantibodies. Upregulation of major histocompatibility complex (MHC) I molecules in vitro and in vivois also a characteristic histological finding, and associated with activation of the Endoplasmic Reticulum (ER) stress response (Nagaraju et al. 2005). Pharmacological activation of the ER stress response is known to cause increased expression of pro-inflammatory muscle-derived cytokines, or myokines (Welc et al. 2013). Based on recent research demonstrating that skeletal muscle acts as a source for many and diverse cytokines, we investigated whether induced MHC I overexpression in myotubes would result in ER stress pathway activation, and release of cytokines.Methods: Murine C2C12 myotubes were transfected with a vector to overexpressing MHC I (H2-kb) using Lipofectamine2000TM transfection reagent with, or without the presence of salubrinal, an ER stress blocking agent. Successful transfection of the MHC I (H2-kb) vector was confirmed using qPCR.  Cellular cytokine gene expression and release was examined using qPCR and Luminex multiplex analysis respectively. ER stress pathway activation was confirmed using qPCR and SDS-PAGE/western blotting. Results: The results show that overexpression of MHC I within C2C12 myotubes results in activation of the ER stress pathway, evidenced by upregulation of the ER stress genes, Grp78, ATF6, PERK, IRE1 and XBP-1. ER stress pathway blocking by salubrinal was confirmed by elevated levels of phosphorylated eif2-alpha. Overexpression of MHC I in C2C12 myotubes also resulted in increased gene expression and release of the potentially chemotactic cytokines IL-6, CCL2, CCL4, CCL5 and CXCL-1. This cytokine expression/release was significantly reduced when transfection occurred in the presence of salubrinal. Conclusion: Our data builds on previous published findings demonstrating that MHC-1 overexpression in skeletal muscle causes ER stress pathway activation. Our results also demonstrate that muscle is potentially a source of various cytokines, a process mediated here via ER stress pathway activation. These findings suggest that muscle cells may exhibit chemotactic capability, so attracting immune cells. Such myokines release suggests muscle may exert paracrine signals on neighbouring fibres, which could contribute to muscle dysfunction in the absence of immune cells. Skeletal muscle may thus act as a source of cytokines in the IIM. Targeted therapies towards myokine production may thus be worthy of further investigation, to further understand muscle dysfunction in IIM.


Disclosure: A. P. Lightfoot, Myositis UK, 2; K. Goljanek-Whysall, None; K. E. Earl, None; C. V. Cotton, None; A. McArdle, None; R. G. Cooper, Myositis UK, 2.

To cite this abstract in AMA style:

Lightfoot AP, Goljanek-Whysall K, Earl KE, Cotton CV, McArdle A, Cooper RG. Investigating the Pathogenic Role of ER Stress Pathway Activation in the Idiopathic Inflammatory Myopathies (IIM): Skeletal Muscle Cells As a Source of Cytokines (Myokines) [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/investigating-the-pathogenic-role-of-er-stress-pathway-activation-in-the-idiopathic-inflammatory-myopathies-iim-skeletal-muscle-cells-as-a-source-of-cytokines-myokines/. Accessed .
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/investigating-the-pathogenic-role-of-er-stress-pathway-activation-in-the-idiopathic-inflammatory-myopathies-iim-skeletal-muscle-cells-as-a-source-of-cytokines-myokines/

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